Genetic aberrations affecting either interferon gamma (IFNgamma) or BRCA1 signaling have been directly implicated in human breast cancer. We have recently identified BRCA1 as coactivator of STAT1 transcription factor, but the complexity of STAT1 regulated gene expression elucidated to date suggests that other components remain to be defined. More recently, it has been shown that human breast cancer cells show the distinct patterns of expression of IFNgamma target genes from normal epithelial cells, implying the correlation of IFNgamma signaling and breast cancer development. Through the analysis of IFN-induced genes, we have identified IFI-16 as a target of IFN/BRCA1 system since BRCA1 binds to and enhances IFI-16-dependent transcriptional regulation. Significantly, we have found that IFI-16 also physically interacts with p53 resulting to synergistic activation, which was further enhanced by BRCA1. We have further discovered that several human breast cancer cell lines examined express quite low level of IFI-16 compared to normal mammary epithelial cells.
Aims of this grant application include exploration of novel functions uncovered by us for a prototype STAT1 transcription factor and BRCA1 breast cancer suppressor protein, structure/function analysis of these proteins. Our goals would be to use this knowledge to investigate novel mechanisms of IFNgamma/STAT1/BRCA1 system in tumor suppression. A second major aim would be the functional analysis of IFI16/BRCA1 and IFI-16/p53 complex. The functions of newly identified IFI-16 in inducing or suppressive aspects of the transformed phenotype in vitro would be explored.
The final aim would be to characterize novel mechanisms of BRCA1 regulation of cell proliferation.
These Aims are supported by our findings of IFNgamma activation of p21WAF1, not other known IFNgamma target promoters, requires wild type BRCA1. Furthermore, we discovered that Fas antigen is a major target of IFI-16, and that expression of IFI-16 causes apoptosis. Taken together with the frequent mutations of BRCA1 locus in familial breast cancer patients, the failure of IFNgamma regulation of cell proliferation due to the loss of BRCA1 could provide insights into the molecular basis for the escape from growth suppression by IFNgamma in tumor evolution as well as the potential for therapeutic intervention with STAT1/BRCA1 signaling. In addition, our previous discovery of p53 activation by BRCA1 strongly supports an idea that there is a functional interaction between the BRCA1/STAT1/IFI-16 signaling cascade and the BRCA1/p53/IFI-16 network, and that the perturbation of this cross talk is closely associated with human cancer development.
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